The present invention relates to novel carbo- and heterocyclic amidines, the preparation thereof and the use thereof as thrombin inhibitors.
Thrombin belongs to the group of serine proteases and plays a central part in the blood coagulation cascade as terminal enzyme. Both the intrinsic and the extrinsic coagulation cascades lead via several amplification stages to the production of thrombin from prothrombin. The thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates the coagulation of blood and the aggregation of the platelets which in turn enhance, owing to the binding of platelet factor 3 and coagulation factor XIII and a whole series of highly active mediators, the formation of thrombin.
The formation and action of thrombin are central events in the production both of white, arterial and of red, venous thrombi and therefore potentially effective points of attack for drugs. Thrombin inhibitors are, in contrast to heparin, able to inhibit completely, independently of cofactors, simultaneously the actions of free thrombin and that bound to platelets. They are able to prevent in the acute phase thromboembolic events after percutaneous trasluminal coronary angioplasty (PTCA) and lysis and to act as anticoagulants in extracorporeal circulation (heart-lung machine, hemodialysis). They can also be generally used for the prophylaxis of thrombosis, for example after surgical operations.
It is known that synthetic arginine derivatives influence the enzymatic activity of thrombin by interacting with the active serine residue of the protease thrombin. Peptides based on Phe-Pro-Art in which the N-terminal amino acid is in the D form have proved to be particularly beneficial. D-Phe-Pro-Arg isopropyl ester has been described as a competitive thrombin inhibitor (C. Mattson et al., Folia Haematol, 109 (1983) 43-51).
Derivatization of the C-terminal arginine to the aldehyde leads to an enhancement of the inhibitory effect. Thus, a large number of arginals able to bind the hydroxyl group of the xe2x80x9cactivexe2x80x9d serine in the form of a hemiacetal have been described (EP 185 390, 479 489, 526 877, 542 525; WO 93/15756, 93/18060).
The thrombin-inhibitory activity of peptide ketones, fluorinated alkyl keteones and of keto esters, boric acid derivatives, phosphoric esters and xcex1-keto carboxamides can likewise be explained by this interaction with serine (EP 118 280, 195 212, 362 002, 364 344, 410 411, 471 651, 589 741, 293 881, 503 203, 504 064, 530 167; WO 92/07869, 94/08941).
DE 31 08 810 and WO 93/11152 describe xcfx89-aminoalkylguanidine dipeptides.
The diphenyl 4-amidinophenylglycinephosphonate peptides described by J. Oleksyszym et al. in J. Med. Chem. 37 (1994) 226-231 are irreversible thrombin inhibitors with inadequate selectivity with respect to other serine proteases.
WO 94/29336 and WO 95/23609 describe benzylamidines as thrombin inhibitors.
The invention relates to compounds of the formula I 
and the salts thereof with physiologically tolerated acids and the stereoisomers thereof, in which the substituents have the following meanings:
R1: H, C1-4-alkyl;
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl; R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94Hxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H, C1-4-alkyl, phenyl-C1-4xe2x80x94alkyl or phenyl, or CF3xe2x80x94COxe2x80x94, C2F5xe2x80x94COxe2x80x94 or C1-4alkylxe2x80x94Oxe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 1, 2, 3 or 4,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-12-alkyl-COxe2x80x94, aryl-COxe2x80x94, aryl-C1-4-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-6-alkyl-COxe2x80x94, HO3Sxe2x80x94C1-3-alkyl-COxe2x80x94, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94, or
xe2x80x83R20R21Nxe2x80x94COxe2x80x94(R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl and R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl, where R20 and R21 may also together be a xe2x80x94(CH2)3-6xe2x80x94 group), or R19xe2x80x94Oxe2x80x94
R4: H, C1-12-alkyl, aryl-C1-4-alkyl or R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl),
R5: H, C1-4-alkyl or benzyl,
R6: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or Nxe2x80x94C1-4-alkyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3xe2x80x94, C1-4-alkoxy, Fxe2x80x94 or Clxe2x80x94,
xe2x80x83R25R26CHxe2x80x94, where R25 is C1-6-alkyl and R26 is H or C1-6-alkyl,
xe2x80x83adamantyl, norbornyl-, 1-decalinyl-, 1-tetralinyl-, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmentyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, phenyl-CH(CH2xe2x80x94CH2xe2x80x94OR19)xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, aryl-Cxe2x89xa1Cxe2x80x94, (CH3)3Sixe2x80x94, R19xe2x80x94Sxe2x80x94CH2xe2x80x94,
xe2x80x83R22Oxe2x80x94C(R23R24)xe2x80x94, where R22 is H, C1-4-alkyl, phenyl, benzyl or C1-4-alkyl-COxe2x80x94, R23 is H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl, phenyl or benzyl and R24 is H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl, phenyl or benzyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl-COxe2x80x94, R19NHxe2x80x94COxe2x80x94C1-4-alkyl, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl, HO3Sxe2x80x94C1-4-alkylxe2x80x94COxe2x80x94, 5-(1H)-tetrazolyl-CH2xe2x80x94 or (R19O)2OPxe2x80x94CH2xe2x80x94 or the acyl radical of a natural or unnatural bile acid,
R8: phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, C1-3-alkyl, C1-3-alkyl-Oxe2x80x94, HOxe2x80x94 or CF3xe2x80x94,
xe2x80x83C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or Nxe2x80x94C1-4-alkyl,
xe2x80x83R25R26CHxe2x80x94 in which R25 is C1-6-alkyl, C5-8-cycloalkyl or phenyl, which can be substituted by 1 to 3 F, Cl, C1-3-alkyl, C1-3-alkyl-Oxe2x80x94, HOxe2x80x94 or CF3, and R26 is H or has one of the meanings stated for R25,
xe2x80x83or R22Oxe2x80x94CH2xe2x80x94, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, C1-4-alkyl-Cxe2x95x90C, aryl-Cxe2x95x90C, (CH3)3Si or dibenzosuberyl which can be monosubstituted on one or both aromatic rings,
R9: H, C1-4-alkyl, aryl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2) 
in which the substitutents R10, R11 and R12, and p, q, r and Y have the following meanings:
p: 0 or 1
q: 1 or 2
r: 1, 2, 3, 4 or 5
Y a methylene group an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl, oxo or C1-4-alkoxy group,
xe2x80x83xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2SOxe2x80x94, xe2x80x94CH2xe2x80x94O, xe2x80x94CHxe2x95x90CHxe2x80x94 or a propylene group, in which the ring resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group or in which a CH2 group can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94SOxe2x80x94,
R10: H, C1-4-alkyl or phenyl,
R11: H, C1-4-alkyl, C3-8-cycloalkyl, phenyl or benzyl,
R12: H, C1-6-alkyl, C3-8-cycloalkyl, phenyl or benzyl, 
in which the substituents have the following meanings:
R13, R14 and R15, which can be identical or different, are H, NO2, F, Cl, Br, I, C3-6-cycloalkyl, R30xe2x80x94Oxe2x80x94, R30OOCxe2x80x94, R30xe2x80x94NHxe2x80x94, R30xe2x80x94COxe2x80x94NHxe2x80x94, where R30 is H, C1-6-alkyl, C3-6-cycloalkyl, benzyl or phenyl, or
xe2x80x83R13 and R14 together are chains xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2Oxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
R16: H, F, Cl, C1-4-alkyl, phenyl-C1-2-alkyl, phenyl, R31OOCxe2x80x94(R31xe2x95x90H, C1-4-alkyl, phenyl or benzyl), R31xe2x80x94NHxe2x80x94, R31xe2x80x94Oxe2x80x94 or R31OOCxe2x80x94CH2xe2x80x94Oxe2x80x94,
R17: H, F, Cl, C1-4alkyl, phenyl-C1-2-alkyl, phenyl, R31OOCxe2x80x94, R31xe2x80x94NHxe2x80x94, R31xe2x80x94Oxe2x80x94 or R31OOCxe2x80x94CH2Oxe2x80x94,
R29: H or C1-4-alkyl, C1-4-alkoxy, C1-4-alkoxy-CO,
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94.
Preferred compounds are from the following groups Ia to Ii: 
In this, the substituents R and A and B have the following meanings:
R2: H, C1-4-alkyl, phenyl and phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H or C1-4-alkyl, CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl or R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl or R20 and R21 together are xe2x80x94(CH2)3-6xe2x80x94 group,
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, where R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, where R25 is C1-6-alkyl, and R26 is H or C1-6-alkyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl, or the acyl radical of a natural or unnatural bile acid,
R8: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene groups(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, where R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, where R25 is C1-6-alkyl, and R26 is H or C1-6alkyl
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2),
The structure IIa to IIc are preferably in the D configuration. 
q: 1 to 2
r: 3 or 4
Y: a methylene group, an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group,
xe2x80x83xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group in which the rings resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group, or in which a xe2x80x94CH2xe2x80x94 group can be replaced by xe2x80x94Oxe2x80x94,
R11: H or C3-6-cycloalkyl,
R12: C1-6-alkyl or C5-6-cycloalkyl,
R13, R14 and R15, which are identical or different: H, R30xe2x80x94Oxe2x80x94 or R30OOCxe2x80x94, where R30 is H, C1-6-alkyl and C3-6-cycloalkyl, and R13 and R14 can together form the chains xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2Oxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, where R13, R14 and R15 are not all hydrogen.
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds Ia are those in which the substituents R and A and B have the following meanings:
R2: H, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21N xe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, or benzyl or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H,
R5: H or CH3xe2x80x94,
R6: C5-8-cycloalkylxe2x80x94, where the aliphatic rings can be substituted by up to 4 C1-4alkyl and/or CH3Oxe2x80x94 groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3xe2x80x94 or CH3Oxe2x80x94, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOCxe2x80x94C1-4-alkyl,
R8: C5-8-cycloalkyl-, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3Oxe2x80x94 groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3xe2x80x94 or CH3Oxe2x80x94, diphenylmethyl dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tertralinyl, 2-tertralinyl or (CH3)3Sixe2x80x94,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: a methylene group, an ethylene group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2Oxe2x80x94 or a propylene group,
R13: H, HO, CH3Oxe2x80x94, EtOxe2x80x94, (CH3)2CHxe2x80x94Oxe2x80x94, Cl, Br or I,
R14: H, HO, CH3Oxe2x80x94 or Cl,
R15: H, HO, CH3Oxe2x80x94 or Cl, where R13, R14 and R15 are not all H.
The structure IIIa is preferably in the L configuration. 
In this, the substituents R, the fragments A and B and X have the following meanings:
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H and C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 and C2F5xe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 to 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19 is preferably H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94 or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOC-C1-4-alkyl, R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl or R20 and R21 together are a xe2x80x94(CH2)3-6xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C3-8-cycloalkyl where the aliphatic rings can be provided with up to 4 C1-4-alkyl and or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, Fxe2x80x94 or Clxe2x80x94,
xe2x80x83R25R26CH13 , in which R25 is C1-6-alkyl, and R26 is H or C1-6-alkyl
R7: H, C1-2-alkyl, C1-20-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl, or the acyl radical of a natural or unnatural bile acid,
R8: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, Fxe2x80x94 or Clxe2x80x94,
xe2x80x83R25R26CHxe2x80x94, in which R25 is C1-6-alkyl, and R26 is H or C1-6-alkyl,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2),
The structures IIa to IIc are preferably in the D configuration. 
q: 1 or 2
r: 3 or 4
Y a methylene group,
an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group, in which the rings resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group, or in which a xe2x80x94CH2xe2x80x94 group can be replaced by xe2x80x94Oxe2x80x94,
R11: H or C3-6-cycloalkyl-,
R12: H, C1-6-akyl or C5-6-cycloalkyl,
R16: H, F, Cl, C1-4-alkyl, R31OOCxe2x80x94, in which R31 is H or C1-4-alkyl, R31xe2x80x94Oxe2x80x94,
R17: H, F, Cl, C1-4-alkyl, R31OOCxe2x80x94 or R31xe2x80x94Oxe2x80x94, where R31 is H or C1-4-alkyl,
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94.
The structure IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds I are those in which the substituents R, the fragments A and B and X have the following meanings:
R2: H, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H,
R5: H or CH3,
R6: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups, and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3xe2x80x94 or CH3Oxe2x80x94, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOCxe2x80x94C1-4-alkyl,
R8: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups, and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3xe2x80x94 or CH3Oxe2x80x94, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopoentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with the formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: a methylene group, an ethylene group xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group,
R16: H,
R17 Hxe2x80x94,
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94.
The structure IIIa is preferably in the L configuration. 
In this, the substituents R and the fragments A and B have the following meanings:
R2: H, C1-4alkyl, phenyl and phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, in which R18 is H and C1-4alkyl, CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94, 
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6alkyl (R19 is preferably H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4alkyl, R19xe2x80x94NHxe2x80x94COxe2x80x94xe2x80x94C1-4-alkyl or R20 and R21 together are a xe2x80x94(CH2)3-6-group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl, which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, in which R25 is C1-6-alkyl, and R26 is H or C1-6-alkyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOC-C1-4-alkyl, R19OOC-C1-4-alkyl-COxe2x80x94, R20R21N-COxe2x80x94, HO3S-C1-4-alkyl-COxe2x80x94, or the acyl radical of a natural or unnatural bile acid,
R8: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or Nxe2x80x94C1-4-alkyl, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl, which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, in which R25 is C1-6-alkyl, and R26 is H or C1-6-alkyl,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2),
The structures IIa to IIc are preferably in the D configuration. 
q: 1 or 2
r: 3 or 4
Y a methylene group,
xe2x80x83an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, or a propylene group, in which the rings resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group, or in which a xe2x80x94CH2xe2x80x94, group can be replaced by xe2x80x94Oxe2x80x94,
R11: H or C3-6-cycloalkyl,
R12: H, C1-6alkyl and C5-6-cycloalkyl,
R16: H, F, Cl, C1-4-alkyl, R31xe2x80x94OOCxe2x80x94, in which R31 is Hxe2x80x94 or C1-4alkyl, or R31xe2x80x94Oxe2x80x94,
R17: H, F, Cl, C1-4-alkyl, R31xe2x80x94OOCxe2x80x94, R31xe2x80x94Oxe2x80x94, where R31 is H or C1-4-alkyl.
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds Ic are those in which the substituents r and the fragments A and B have the following meanings:
R2: Hxe2x80x94, 
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl or R20 and R21 together are a xe2x80x94(CH2)4-5-group),
R4: H,
R5: H, or CH3xe2x80x94,
R6: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups, and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetra-linyl or (CH3)3Sixe2x80x94,
R7: H, C1-6-alkyl or R19OOC-C1-4-alkyl,
R8: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups, and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: a methylene group, an ethylene group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group,
R16: H,
R17: H.
The structure IIIa is preferably in the L configuration. 
In this, the substituents R, A, B and X have the following meanings:
R2: H, C1-4-alkyl, phenyl and phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94CO, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, in which R18 is H and C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 and C2F5xe2x80x94COxe2x80x94, 
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19 is preferably H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl, R19-NHxe2x80x94COxe2x80x94C1-4alkyl or R20 and R21 together are a xe2x80x94(CH2)3-6-group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94,
xe2x80x83C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R2Oxe2x80x94C(R23R24)-, which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, which R25 C1-6-alkyl, and R26 is H or C1-6-alkyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOC-C1-4alkyl, R19OOC-C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl-COxe2x80x94, or the acyl radical of a natural or unnatural bile acid,
R8: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O rings, and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monsubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with the formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
q: 1 or 2
r: 3 or 4
Y a methylene group,
xe2x80x83an ethylene in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group, in which the rings resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group, or in which a CH2 group can be replaced by xe2x80x94Oxe2x80x94,
R11: H or C3-6-cycloalkyl,
R12: H, C1-6-alkyl or C5-6-cycloalkyl,
R16: H, F, Cl, C1-4-alkyl, R31xe2x80x94OOCxe2x80x94, in which R31 is H or C1-4-alkyl, or R31xe2x80x94Oxe2x80x94,
R17: H, F, Cl, C1-4-alkyl, R31xe2x80x94OOCxe2x80x94 or R31xe2x80x94Oxe2x80x94, where R16 and R17 are not both H and not both F, and R31 is H or C1-4-alkyl.
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94.
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds Id are those the substituents R, A, B and X have the following meanings:
R2: H 
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl or R20 and R21 together are a xe2x80x94(CH2)4-5-group),
R4: H,
R4: H or CH3,
R6: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOC-C1-4-alkyl,
R8: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4alkyl and/or CH3O groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with the formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: a methylene group, an ethylene group xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2Oxe2x80x94 or a propylene group,
R16: H, C1, C1-4-alkyl or CH3O,
R16: H, Cl, C1-4-alkyl or CH3O, where R16 and R17 are not both H,
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94,
The structure IIIa is preferably in the L configuration. 
In this, the substituents R, the fragments A and B and X have the following meanings:
a)
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, in which R18 is H or C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6alkyl (R19xe2x95x90H, C1-4alkyl, benzyl), HO3S-C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94 or benzyl-OOCxe2x80x94, R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl and R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl, or R20 and R21 together are a xe2x80x94(CH2)3-6-group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C5-8-cycloalkyl, where the alkphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups and/or one or more CH2 group(s) is(are) replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, diphenylmethyl, dicyclo-hexylmethyl, dibenzosuberyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, Me3Si, or
R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl and R23 and R24 are H, C1-4-alkyl or phenyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOC-C1-4-alkyl, R19OOC-C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl-COxe2x80x94, or the acyl radical of a natural or unnatural bile acid,
R8: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups and/or one or more CH2 group(s) is(are) replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, diphenylmethyl, dicyclohexylmethyl, dibenzosuberyl, phenyl-C(CH3)2xe2x80x94, C1-4alkyl-Cxe2x89xa1Cxe2x80x94, Me3Si, or R22Oxe2x80x94C(R23R24)xe2x80x94,
R9: C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with the formula IIc be a substituent on all ring positions apart from position 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
q: 1 or 2
r: 3 or 4
Y a methylene group,
xe2x80x83an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group, in which the rings resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group, or in which one CH2 group can be replaced by xe2x80x94Oxe2x80x94,
R11: H or C3-6-cycloalkyl,
R12: H, C1-6-alkyl or C5-6-cycloalkyl,
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94.
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds Ie listed under a) are those in which the substituents R, the fragments A and B and X have the following meanings:
R2: H, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl, or R20 and R21 together are a xe2x80x94(CH2)4-5-group),
R4: H,
R5: H or CH3,
R6: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups, and/or one CH2 group is replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of CH3, CF3, CH3O, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, diphenylmethyl, dicyclohexylmethyl, Me3Si or tert-butoxymethyl,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOCxe2x80x94C1-4-alkyl,
R8: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups, and/or one CH2 group is replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of CH3, CF3, CH3O, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, diphenylmethyl, dicyclohexylmethyl, Me3Si or tert-butoxymethyl,
R9: C1-4-alkyl, phenyl, or C5-6-cycloalkyl (R9 can in acordance with the formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: a methylene group, an ethylene group, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group,
X: xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94.
The structure IIIa is preferably in the L configuration or in the compound Ie the substituents R, the fragments A and B and X have the following meanings:
b)
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94CO, R18xe2x80x94NHxe2x80x94COxe2x80x94CO, in which R18 is H and C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 and C2F5xe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19 is preferably H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl, R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl or R20 and R21 together are a xe2x80x94(CH2)3-6-group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C3-8cycloalkyl which can be substituted by up to 4 C1-4-alkyl and/or CH3O groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94 or R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, in which R25 is C1-6-alkyl, C5-8-cycloalkyl or phenyl which can be substituted by 1 to 3 F, Cl, C1-3-alkyl, C1-3-alkyl-Oxe2x80x94, HO or CF3, and R26 is H or has one of the meanings stated for R25,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOC-C1-4-alkyl, R19OOC-C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl-COxe2x80x94, or the acyl radical of a natural or unnatural bile acid,
R8: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94,
xe2x80x83R25R26CHxe2x80x94, in which R25 is C1-6-alkyl, C6-8-cycloalkyl or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, C1-3-alkyl, C1-3-alkyl-Oxe2x80x94, HO or CF3, or R22Oxe2x80x94CH2xe2x80x94, in which R22 has the abovementioned meanings,
xe2x80x83adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with the formula IIc be a substituent on all ring positions apart from positions 1 and 2),
the structures IIa to IIc are preferably in the D configuration. 
R11: H or C3-6-cycloalkyl
R12: C1-6-alkyl or C5-6-cycloalkyl-
Y: xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group in which the rings resulting therefrom can carry on the carbon atom in position 3 and/or 4 a C1-4-alkyl group, or in which a CH2 group can be replaced by xe2x80x94Oxe2x80x94,
X: xe2x95x90CHxe2x80x94, or xe2x95x90Nxe2x80x94.
Particularly preferred compounds Ie are those detailed under b), in which the substituents R and A and B have the following meanings:
R2: Hxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl or R20 and R21 together are a xe2x80x94(CH2)4-4xe2x80x94 group),
R4: H,
R5: H or CH3,
R6: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups, and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl, which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOCxe2x80x94C1-4-alkyl,
R8: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups, and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl, which can be substituted by i to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group,
X: xe2x95x90CHxe2x80x94or xe2x95x90Nxe2x80x94,
The structure IIIa is preferably in the L configuration.
If: 
In this, the substituent R and A and B have the following meanings:
a)
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H, C1-4-alkyl, phenyl-C1-4-alkyl or phenyl, or CF3xe2x80x94COxe2x80x94, C2F5xe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94,
xe2x80x83R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl or R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5 H or C1-4-alkyl,
R6: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups and/or one or more xe2x80x94CH2 group(s) is(are) replaced by xe2x80x94Oxe2x80x94 or phenyl which is substituted by 2 or 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, diphenylmethyl, dicyclohexylmethyl, dibenzosuberyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, Me3Si or
xe2x80x83R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl or phenyl,
R7: Hxe2x80x94, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl-COxe2x80x94, and the acyl radical of a natural or unnatural bile acid,
R8: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups and/or one or more xe2x80x94CH2 group(s) is(are) replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, diphenylmethyl, dicyclohexylmethyl, dibenzosuberyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, Me3Si or
R9: C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2),
the structures IIa to IIc are preferably in the D configuration. 
q: 1 or 2
r: 3 or 4
Y a methylene group,
xe2x80x83an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group,
xe2x80x83xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group, in which the rings resulting therefrom can carry on the carbon atom in position 3 and/or 4 a C1-4-alkyl group, or in which one xe2x80x94CH2xe2x80x94 group can be replaced by xe2x80x94Oxe2x80x94,
R11: H or C3-6-cycloalkyl,
R12: H, C1-6-alkyl or C5-6-cycloalkyl,
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds If are those listed under a) in which the substituents R and the fragments A and B have the following meanings:
R2: H, 
in which the substituents have the following meanings:
m: 0 or 1,
N: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl, or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H,
R5 H or CH3,
R6: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups, and/or a CH2 group is replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of CH3, CF3, CH3O, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, diphenylmethyl, dicyclohexylmethyl, Me3Sixe2x80x94 or tert-butoxymethyl,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOCxe2x80x94C1-4-alkyl,
R8: C5-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups, and/or a CH2 group is replaced by xe2x80x94Oxe2x80x94, or phenyl which is substituted by 2 or 3 identical or different radicals from the group of CH3, CF3, CH3O, P or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, diphenylmethyl, dicyclohexylmethyl, Me3Sixe2x80x94 or tert-butoxymethyl,
R9: C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: a methylene group, an ethylene group, xe2x80x94CHxe2x95x90CH , xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group.
The structure IIIa is preferably in the L configuration,
or
in the compound the substituents K and the fragments A and B have the following meanings:
b)
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18Oxe2x80x94COxe2x80x94CO, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, in which R18 is H and C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 and C2F5xe2x80x94COxe2x80x94, 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-12-alkyl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-6-alkyl (R19 is preferably H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-7-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl, R19xe2x80x94NHxe2x80x94COxe2x80x94C1-4-alkyl or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-4-alkyl,
R5: H or C1-4-alkyl,
R6: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4-alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl, phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
R25R26CH, in which R25 is C1-4-alkyl and R26 is H or C1-6-alkyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl, R19OOCxe2x80x94C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl-COxe2x80x94, or the acyl radical of a natural or unnatural bile acid,
R8: C3-8-cycloalkyl, where the aliphatic rings can be provided with up to 4 C1-4-alkyl and/or CH3O groups and one or more methylene group(s) can be replaced by xe2x80x94Oxe2x80x94, or adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, diphenylmethyl which can be monosubstituted on one or both rings, dicyclohexylmethyl, phenyl-C(CH3)2xe2x80x94, C1-4-alkyl-Cxe2x89xa1Cxe2x80x94, R22Oxe2x80x94C(R23R24)xe2x80x94, in which R22 is H or C1-4 alkyl, and R23 and R24 are H, C1-4-alkyl, HOxe2x80x94C1-3-alkyl or phenyl,
xe2x80x83phenyl which can be substituted by up to 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or Cl,
xe2x80x83R25R26CHxe2x80x94, in which R25 is C1-6-alkyl and R26 is H or C1-6-alkyl,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
q: 1 or 2
r: 3 or 4
Y xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group, in which the rings resulting therefrom can carry on the carbon in position 3 and/or 4 a C1-4-alkyl group, or in which xe2x80x94CH2 group can be replaced by xe2x80x94Oxe2x80x94.
R11: H or C3-6-cycloalkyl,
R12: H, C1-6-alkyl or C5-6-cycloalkyl,
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred compounds if listed under b) are those in which the substituents R, the fragments A and B and X have the following meanings:
b)
R2: H 
in which the substituents have the following meanings:
m: 0 or 1,
n: 2 or 3,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-6-alkyl (R19 is H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H
R5: H or CH3,
R6: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R7: H, C1-6-alkyl-COxe2x80x94 or R19OOCxe2x80x94C1-4-alkyl,
R6: C5-8-cycloalkyl, where the aliphatic rings can be substituted by up to 4 C1-4-alkyl and/or CH3O groups and in which one methylene group can be replaced by xe2x80x94Oxe2x80x94, or phenyl which can be substituted by 1 to 3 identical or different radicals from the group of F, Cl, CH3 or CH3O, diphenylmethyl, dicyclohexylmethyl, isopropyl, tert-butyl, neopentyl, tert-butoxymethyl, phenoxymethyl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl or (CH3)3Sixe2x80x94,
R9: H, C1-4-alkyl, phenyl or C5-6-cycloalkyl (R9 can in accordance with formula IIc be a substituent on all ring positions apart from positions 1 and 2).
The structures IIa to IIc are preferably in the D configuration. 
Y: xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or a propylene group.
The structure IIIa is preferably in the L configuration. 
In this, the substituents R and the function of Y have the following meanings:
a)
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is or C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94,
R3: R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90Hxe2x80x94, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-2-alkyl, or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-2-alkyl,
R6: H, C1-12-alkyl and
Y: xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94. 
The amino acid containing Y is preferably in the L configuration
Particularly preferred compounds Ig listed under a) are those in which the substituents R and the function of Y have the following meanings:
a)
R2: H,
R3: R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90Hxe2x80x94, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, or benzyl, or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H,
R6: H, C1-4-alkyl and
Y: xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
The amino acid containing Y is preferably in the L configuration.
or
in the compound Ig, the substituents R and Y have the following meanings:
b)
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H or C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94,
R3: H, C1-12-alkyl, aryl-C1-2-alkyl, R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-4-alkyl-OOCxe2x80x94, benzyl-OOCxe2x80x94 or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-2-alkyl, or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-2-alkyl,
R6: H, C1-12-alkyl and
Y: an ethylene group in which the ring resulting therefrom carries in position 4 a hydroxyl or C1-4-alkoxy group, or xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or a propylene group in which one CH2 group is replaced by xe2x80x94Oxe2x80x94or xe2x80x94Sxe2x80x94.
The amino acid containing Y is preferably in the L configuration.
Particularly preferred compounds Ig listed under b) are those in which the substituents R and the function of Y have the following meanings:
R2: H,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl or benzyl, or R20 and R21 together are a xe2x80x94(CH2)4-4xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-2-alkyl,
R6: H, C1-4-alkyl and
Y: xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94.
The amino acid containing Y is preferably in the L configuration. 
In this, the substituents R and B have the following meanings:
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl,
R18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18xe2x80x94NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H or C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94, 
R3: H, C1-12-alkyl, aryl-C1-2-alkyl, R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, C1-4-alkylxe2x80x94OOCxe2x80x94, benzyl-OOCxe2x80x94 or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl, aryl, aryl-C1-2-alkyl, or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H, C1-12-alkyl or aryl-C1-2-alkyl,
R5: C1-4-alkyl,
R6: H, C1-12-alkyl. 
q: 1 or 2
r: 3 or 4
H or C3-6-cycloalkyl,
R12: H, C1-6-alkyl or C5-6-cycloalkyl,
Y: a methylene group,
xe2x80x83an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group,
xe2x80x83xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or a propylene group in which one xe2x80x94CH2xe2x80x94 group can, be replaced by xe2x80x94Oxe2x80x94or xe2x80x94Sxe2x80x94.
xe2x80x83The structures IIIA to IIIf are preferably in the L configuration.
Particularly preferred compounds Ia are those in which the substituents R and B have the following meanings:
R2: H,
R3: H, C1-6-alkyl, benzyl, R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), HO3Sxe2x80x94C1-3-alkyl, or R20R21Nxe2x80x94COxe2x80x94 (R20 and R21 are identical or different and are H, C1-6-alkyl or benzyl, or R20 and R21 together are a xe2x80x94(CH2)4-5xe2x80x94 group),
R4: H,
R5: CH3,
R6: H, C1-4-alkyl. 
Y: a methylene group, an ethylene group, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94or a propylene group.
The structure IIIa is preferably in the L configuration. 
In this, the substituents R, the fragment B and m have the following meanings:
m: 0, 1
R2: H, C1-4-alkyl, phenyl, phenyl-C1-4-alkyl, R 18Oxe2x80x94CH2xe2x80x94, R18xe2x80x94COxe2x80x94, R18xe2x80x94Oxe2x80x94CH2xe2x80x94COxe2x80x94, R18-NHxe2x80x94COxe2x80x94COxe2x80x94, where R18 is H or C1-4-alkyl, or CF3xe2x80x94COxe2x80x94 or C2F5xe2x80x94COxe2x80x94,
R5: H or C1-4-alkyl,
R7: H, C1-12-alkyl, C1-20-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl (R19xe2x95x90H, C1-4-alkyl, benzyl), R19OOCxe2x80x94C1-4-alkyl-COxe2x80x94, R20R21Nxe2x80x94COxe2x80x94, HO3Sxe2x80x94C1-4-alkyl, and the acyl radical of a natural or unnatural bile acid (R20, R21 are identical or different and are H, C1-6-alkyl or benzyl, or R20 and R21 together are a -(CH2)4-5- group),
R8: C3-8-cycloalkyl, where the aliphatic rings are provided with up to 4 C1-4-alkyl and/or CH3O groups, and/or one or more methylene group(s) is (are) replaced by xe2x80x94Oxe2x80x94, or
xe2x80x83phenyl which is substituted by 2 or 3 identical or different radicals from the group of C1-4-alkyl, CF3, C1-4-alkoxy, F or C1,
xe2x80x83adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, 1-indanyl, 2-indanyl, (CH3)3Sixe2x80x94, diphenylmethyl, dicyclohexylmethyl or dibenzosuberyl, which can be monosubstituted on one or both aromatic rings, 
q: 1 or 2
r: 3 or 4
y: a methylene group,
xe2x80x83an ethylene group in which the ring resulting therefrom can carry in position 4 a hydroxyl or C1-4-alkoxy group,
xe2x80x83xe2x80x94CH2-Sxe2x80x94, xe2x80x94CH2-Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or propylene group in which one xe2x80x94CH2 group can be replaced by xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
R11: H or C3-6-cycloalkyl
R12: H, C1-6-alkyl, C5-6-cycloalkyl.
The structures IIIa to IIIf are preferably in the L configuration.
Particularly preferred copounds Ii are those in which the substituents R and the fragment B have the following meanings:
R2: H,
R5: H or CH3,
R7: H, C1-6-alkyl-COxe2x80x94, R19OOCxe2x80x94C1-4-alkyl, (R19xe2x95x90H, C1-4-alkyl, benzyl)
R8: C5-8-cycloalkyl, where the aliphatic rings are substitued by up to 4 CH3 and/or CH3O groups, and/or one methylene group is replaced by xe2x80x94Oxe2x80x94, or
xe2x80x83phenyl, which is substitued by 2 or 3 identical or different radicals from the group of CH3, CF3, CH3O, F or Cl, adamantyl, norbornyl, 1-decalinyl, 1-tetralinyl, 2-tetralinyl, diphenylmethyl, dicyclohexylmethyl, Me3Si or tert-butoxymethyl, 
Y: a methylene group, an ethylene group, xe2x80x94CH2-Sxe2x80x94, xe2x80x94CH2-Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or a propylene group.
The structure IIIa is preferably in the L configuration.
The term xe2x80x9calkylxe2x80x9d used above describes straight-chain and branched carbon frameworks. Aryl means carbo- and heterocyclic aromatic systems which can be mono- or bicyclic.
Preferred structures of the invention are:
(D)-(Cyclohexyl)Hyac-Pro-NH-3-(6-am)-pico
(D)-(Cyclohexyl)Hyac-Pro-NH-4-amb
(D)-(Cyclohexyl)Hyac-Pro-NH-(2-MeO)-4-amb
(D)-(Cyclohexyl)Hyac-Aze-NH-4-amb
(D)-(3-Phenyl)Hyac-Pro-NH-4-amb
(D,L)-(1-Tetralinyl)Hyac-Pro-NH-3-(6-am)-pico
(D,L)-(1-Tetralinyl)Hyac-Pro-NH-4-amb
O-Acetyl-(D)-(Cyclohexyl)Hyac-Pro-NH-3-(6-am)-pico
O-Acetyl-(D)-(Cyclohexyl)Hyac-Pro-NH-4-amb
O-Hexanoyl-(D)-(Cyclohexyl)Hyac-Pro-NH-4-amb
O-Hydroxycarbonyl-methyl-(D)-(Cyclohexyl)Hyac-Pro-NH-3-(6-am)-pico
(D)-(xcex2-Cyclohexyl)Hypr-Pro-NH-3-(6-am)-pico
(D)-(xcex2-Cyclohexyl)Hypr-Pro-NH-4-amb
(D)-(xcex2-Cyclohexyl)Hypr-Pro-NH-(2-MeO)-4-amb
(D,L)-(xcex2,xcex2-Diphenyl)Hypr-Pro-NH-3-(6-am)-pico
(D,L)-(xcex2,xcex2-Diphenyl)Hypr-Pro-NH-4-amb
(D,L)-(xcex2,xcex2-Dicyclohexyl)Hypr-Pro-NH-3-(6-am)-pico
H-(D)-Chg-Aze-NH-3-(6-am)-pico
H-(D)-Chg-Pic-NH-3-(6-am)-pico
H-(D)-Cha-Pro-NH-3-(6-am)-pico
H-(D)-(tert.Butyl)Ser-Pro-NH-3-(6-am)-pico
H-(D)-Chg-Hyp-NH-3-(6-am)-pico
H-(D)-Chg-1-Tic-NH-3-(6-am)-pico
H-(D)-Chg-3-Tic-NH-3-(6-am)-pico
H-(D)-Chg-2-Phi-NH-3-(6-am)-pico
H-(D,L)-Chea-Pro-NH-3-(6-am)-pico
H-(D)-(xcex1-Me)Cha-Pro-NH-3-(6-am)-pico
H-D,L-4-Tetrahydropyranyl)-Gly-Pro-NH-3-(6-am)-pico
H-(+/xe2x88x92)-(threo)-(xcex2-Hydroxy)-Phe-Pro-NH-3-(6-am)-pico
H-(D,L)-(2-Norbornyl)Gly-Pro-NH-3-(6-am)-pico
H-(D,L)-(1-Adamantyl)Gly-Pro-NH-3-(6-am)-pico
H-(D,L)-(1-Tetralinyl)Gly-Pro-NH-3-(6-am)-pico
H-(D,L)-(Me3Si)Ala-Pro-NH-3-(6-am)-pico
H-(D,L)-(3,4,5-Trimethoxy)Phe-Pro-NH-3-(6-am)-pico
H-(D,L)-(3-Phenyl)Pro-Pro-NH-3-(6-am)-pico
H-(D,L)-(4-Me)Pic-Pro-NH-3-(6-am)-pico
H-(D)-Cha-Pyr-NH-3-(6-am)-pico
H-(D)-Chg-(N-Cyclopropyl)Gly-NH-3-(6-am)-pico
H-(D)-Chg-(Cyclo)Leu-NH-3-(6-am)-pico
H-(D)-Chg-Pro-NH-5-(2-am)-pym
H-(D)-Chg-Pro-NH-2-(5-am)-pym
H-(D)-Chg-Pro-NH-(4-am)-napme
H-(D,L)-Thpg-Pro-NH-(2-Meo)-4-amb
H-(D,L)-Dpa-Pro-NH-(2-MeO)-4-amb
H-(D,L)-(2-Norbornyl)Gly-Pro-NH-(2-MeO)-4-amb
H-(D,L)-(1-Tetralinyl)Gly-Pro-NH-(2-MeO)-4-amb
H-(D,L)-Cog-Pro-NH-(2-Meo)-4-amb
H-(D)-(xcex1-Me)Cha-Pro-NH-(2-MeO)-4-amb
H-(D,L)-(Dibenzosuberyl)Gly-Pro-NH-(2-MeO)-4-amb
H-(D,L)-(3,4,5-Trimethoxy)Phe-Pro-NH-(2-MeO)-4-amb
H-(D,L)-(Me3Si)Ala-Pro-NH-(2-MeO)-4-amb
H-(+/xe2x88x92threo)-(3-Hydroxy)Phe-Pro-NH-(2-MeO)-4-amb
H-(D)-(tert-Butyl)Ser-Pro-NH-(2-MeO)-4-amb
H-(D,L)-(3-Phenyl)Pro-Pro-NH-(2-MeO)-4-amb
H-(D)-Chg-Pic-NH-(2-MeO)-4-amb
H-(D)-Chg-Pyr-NH-(2-MeO)-4-amb
H-(D)-Chg-(N-cyclopropyl)Gly-NH-(2-MeO)-4-amb
H-(D)-Chg-1-Tic-NH-(2-MeO)-4-amb
H-(D)-Cha-Pic-NH-(2-MeO)-4-amb
H-(D)-Chg-Pro-NH-(2-EtO)-4-amb
H-(D)-Chg-Pro-NH-(2-I)-4-amb
H-(D)-Chg-(Cyclo)Leu-NH-(2-MeO)-4-amb
H-(D)-Chg-Pro-NH-(2-OH)-4-amb
H-(D)-Chg-Pro-NH-(2,6-Dimethoxy)-4-amb
H-(D)-Chg-Pro-NH-(3-MeO)-4-amb
H-(D)-Chg-Pro-NH-(3-OH)-4-amb
H-(D)-Chg-Pro-NH-(3-Cl)-4-amb
H-(D)-Chg-Pro-NH-(2-COOH)-4-amb
H-(D)-Chg-Pro-NH-(2-NH2)-4-amb
H-(D)-Chg-Pro-NH-(2-OCH2-COOH)-4-amb
HOOC-CH2-(D)-Cha-Pro-NH-(2-MeO)-4-amb
MeOOC-CH2-(D)-Cha-Pro-NH-(2-MeO)-4-amb
HOOC-CH2-CH2-(D)-Chg-Pro-NH-(2-MeO)-4-amb
tBuOOC-CH2-(D,L)-Cog-Pro-NH-(2-MeO)-4-amb
HOOC-CH2-(D,L)-Cog-Pro-NH-(2-MeO)-4-amb
HOOC-CH2-(D,L)-Dpa-Pro-NH-(2-MeO)-4-amb
Cbz-(D)-(tert-Butyl)Ser-Pro-NH-(2-MeO)-4-amb
HOOC-CH2-(D)-Cha-Pic-NH-(2-MeO)-4-amb
Ph-CH2-(D)-Chg-Pro-NH-(2-MeO)-4-amb
HOOC-CH2-(D)-Chg-Pro-NH-(2-OH)-4-amb
HOOC-CH2-(D)-Cha-Pro-NH-(2-OH)-4-amb
HOOC-CH2-(D)-Chg-Pro-NH-(2-Cl)-4-amb
HOOC-CH2-(D,L)-(4-Me)Chg-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(4-iPr)Chg-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(4-tBu)Chg-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-Dch-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(3,3-Dimethyl)Chg-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D)-(tert-Butyl)Ser-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-Cpg-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(1-Tetralinyl)Gly-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(2-norbornyl)Gly-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(Thpg)-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(Thpa)-Pro-NH-3-(6-am)-pico
tBuOOC-CH2-(D,L)-(Thpg)-Pic-NH-3-(6-am)-pico
HOOC-CH2-(L)-(Thpg)-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D)-(Thpg)-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(Thpg)-Oxp-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(Thpa)-Oxp-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-Chg-Thia-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Chg-Pro-NH-3-(6-ham)-pico
BnOOC-CH2-(D)-Chg-Pro-NH-3-(6-ham)-pico
MeOOC-CH2-(D)-Chg-Pro-NH-3-(6-methoxycarbonyl-am)-pico
tBuOOC-CH2-(D)-(tBu)Gly-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D)-(tBu)Gly-Pic-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-(neo-Pentyl)Gly-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D)-(neo-Pentyl)Gly-Pic-NH-3-(6-am)-pico
HOOC-CH2-CH2-(D)-Chg-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D)-(3,4,5-Trimethoxy)Phe-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D)-Chg-Pro-NH-3-(6-am-2-MeO)-pico
HOOC-CH2-(D)-Cha-Pro-NH-3-(6-am-2-Me)-pico
HOOC-CH2-(D)-Chg-Pro-NH-3-(6-am-4-MeO)-pico
HOOC-CH2-(D)-Chg-Pro-NH-(6-am-4-Me)-pico
HOOC-CH2-(D)-Cha-Pyr-NH-(2-MeO)-4-amb
HOOC-CH2-(D)-Cha-Pyr-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(Thpa)-Pyr-NH-3-(6-am)-pico
iPrOOC-CH2-(D)-Chg-Pyr-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-(xcex3-Me)Cha-Pyr-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-Chea-Pyr-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Chg-Oxp-NH-3-(6-am)-pico
HOOC-CH2-(D)-Chg-Oxp-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Cha-Oxp-NH-3-(6-am)-pico
HOOC-CH2-(D)-Cha-Oxp-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Chg-Pro-NH-3-(6-am)-pico
MeOOC-CH2-(D)-Chg-Pro-NH-3-(6-am)-pico
CyclohexylOOC-CH2-(D)-Chg-Pro-NH-3-(6-am)-pico
(tBuOOC-CH2)2-(D)-Chg-Pro-NH-3-(6-am)-pico
(HOOC-CH2)2-(D)-Chg-Pro-NH-3-(6-am)-pico
H2NCO-CH2-(D)-Chg-Pro-NH-3-(6-am)-pico
tBuNHCO-CH2-(D)-Chg-Pro-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Chg-Aze-NH-3-(6-am)-pico
HOOC-CH2-(D)-Chg-Aze-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Chg-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D)-Chg-Pic-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Cha-Pro-NH-3-(6-am)-pico
HOOC-CH2-(D)-Cha-Pro-NH-3-(6-am)-pico
tBuOOC-CH2-(D)-Cha-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D)-Cha-Pic-NH-3-(6-am)-pico
HOOC-CH2-(D,L)-Cog-Pro-NH-5-(2-am)-pym
List of Abbreviations:
The invention furthermore relates to the compounds of the formulae 
where A, B, X, R1, R2, R13, R14, R15, R16 and R17 have the stated meaning, and E is 
and in which the amidino functionality in formulae VI, X, XI and XII can be in mono- or diprotected form.
Particularly suitable protective groups for the protected form are the Cbz and Boc groups.
The novel intermediates are used to prepare the compounds I and are valuable building blocks for synthesizing serine protease inhibitors.
The structural fragment of the formula XIV 
in which D has the abovementioned meaning, is novel and is valuable as constituent of serine protease inhibitors and in particular of thrombin inhibitors.
The compounds of the formula I may exist as such or in the form of their salts with physiologically tolerated acids. Examples of such acids are: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
The novel compounds can be used for the therapy and prophylaxis of thrombin-dependent thromboembolic events such as deep vein thromboses, pulmonary embolisms, myocardial or cerebral infarcts and unstable angina, also for the therapy of disseminated intravascular coagulation (DIC). They are furthermore suitable for combination therapy with thrombolytics such as streptokinase, urokinase, prourokinase, t-PA, APSAC and other plasminogen activators for shortening the reperfusion time and prolonging the reocclusion time.
Other areas of use are the prevention of thrombin-dependent early reocclusion and late restenosis after percutaneous transluminal coronary angioplasty, the prevention of thrombin-induced proliferation of smooth muscle cells, the prevention of the accumulation of active thrombin in the CNS (eg. in Alzheimer""s disease), the control of tumors and the prevention of mechanisms which lead to adhesion and metastasis of tumor cells.
Their particular advantage is that they are also effective after oral administration.
The compounds according to the invention can be administered in a conventional manner orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally). Administration can also take place with vapors or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient per person is about 10-2000 mg on oral administration and about 1-200 mg of parenteral adminstration. This dose can be given in 2 to 4 single doses or once a day as depot form.
The novel compounds can be used in conventional solid or liquid pharmaceutical forms, eg. as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be mixed with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain from 0.1 to 99 percent by weight of active ingredient.
Experimental Part:
The compounds of the formula I can be prepared starting from the N-terminally protected xcex1-amino acids or xcex1-hydroxy carboxylic acids A-OH, the xcex1-amino acid B-OH and the building block H2N-C(R1R2)-E as shown in scheme 1 and 2. Classical methods of protective group and coupling chemistry are used for this purpose.
The radicals R3 and R4 or R7 can alternatively be introduced after the coupling of the building blocks A-OH, B-OH and H2N-C(R1R2)-E to give A-B-N-C(R1R2)-E after cleavage of the protective group from A or are a constituent of A-OH from the outset. 
where W is one of the conventional N-terminal protective groups (preferably Boc or Cbz) and Wxe2x80x2 is methyl, ethyl, tert-butyl or benzyl.
The required coupling reactions and the conventional reactions for introducing and eliminating protective groups are carried out under standard conditions of peptide chemistry (see M. Bondanszky, A. Bodanszky xe2x80x9cThe Practice of Peptide Synthesisxe2x80x9d, 2nd edition, Springer Verlag Heidelberg, 1994).
Boc protective groups are elminated using dioxane/HCl or TFA/DCM, and Cbz protective groups are eliminated by hydrogenolysis or with HF. The hydrolysis of ester functionalities takes place with LiOH in an alcoholic solvent or in dioxane/water. t-Butyl esters are cleaved with TFA.
N-terminal alkyl radicals (see R3 and R4) are introduced by reductive alkylation or direct N-alkylation.
Alkanoyl radicals (see R7) are introduced by standard coupling reactions or esterification reactions.
The amidino functionality can be prepared from a nitrile functionality by several methods:
One method is classical Pinner synthesis (R. Boder, D. G. Neilson Chem. Rev. 61 (1961) 179) or a modified Pinner synthesis which passes through imino thioester salts as intermediate (H. Vieweg et al. Pharmazie 39 (1984), 226). Catalytic hydrogenation of N-hydroxyamidines, which are obtainable by addition of hydroxylamine onto the cyano group, with Raney nickel or Pd/C in alcoholic solvents likewise results in amidines (B. J. Broughton et al. J.Med.Chem. 18 (1975), 1117) and is particularly valuable for the synthesis of pharmaceutically active compounds.
The reactions were checked by TLC, normally using the following mobile phases:
Where separations by column chromatography are mentioned, these were separations on silica gel using the abovementioned mobile phases.
Reversed phase HPLC separations were carried out with acetonitrile/water and HOAc buffer.
The starting compounds can be prepared by the following methods:
A wide variety of possibilities is available in the literature for the general and specific synthesis of amino acids. A summary thereof is provided, inter alia, by Houben-Weyl, volume E16d/part 1, pages 406 et seq.
Frequently used precursors were N-(diphenylmethylene)glycine ethyl ester, diethyl acetamidomalonate and ethyl isocyanoacetate.
Various glycine and alanine derivatives were prepared, for example, starting from ethyl isocyanoacetate and an appropriate ketone or aldehyde (see H.-J. Prxc3xa4torius, J. Flossdorf, M.-R. Kula Chem. Ber. 108 (1975) 3079).
Boc-Cyclooctylglycine, Boc-2-norbornylglycine, Boc-adamantylalanine, Boc-xcex3-methylcyclohexylalanine and Boc-(4-Me)cyclohexylglycine were synthesized via the corresponding ethyl 2-formylaminoacrylates (U. Schxc3x6llkopf and R. Meyer, Liebigs Ann. Chem. (1977) 1174) starting from ethyl isocyanoacetate with the respective carbonyl compounds cyclooctanone, 2-norbornanone, 1-formyladamantane, 1-formyl-1-methylcyclohexane, and 4-methylcyclohexanone by the following general methods:
General Method for Synthesizing the ethyl 2-formylaminoacrylates
A solution of 100 mmol of ethyl isocyanoacetate in 50 ml of THF is added dropwise to 100 mmol of potassium tert-butoxide in 150 ml of THF at 0 to xe2x88x9210xc2x0 C. After 15 min, 100 mmol of the appropriate carbonyl compound in 50 ml of THF is added at the same temperature, the reaction mixture is slowly allowed to rise to RT and the solvent is stripped off in a rotary evaporator. The residue is mixed with 50 ml of water, 100 ml of acetic acid and 100 ml of DCM and the product is extracted with DCM. The DCM phase is dried over Na2SO4, and the solvent is stripped off in a rotary evaporator. The resulting products are almost pure and can, if required, be further purified by column chromatography on silica gel (mobile phase: ethyl/petroleum ether mixtures).
General Method for Amino Acid Hydrochlorides Starting from the ethyl 2-formylaminoacrylates
100 mmol of ethyl 2-formylaminoacrylates are hydrogenated with Pd/C (10%)/hydrogen in 200 ml of glacial acetic acid until conversion is complete. The catalyst is then filtered off, the acetic acid is stripped off as far as possible in a rotary evaporator, and the residue is refluxed in 200 ml of 50% concentrated hydrochloric acid for 5 h. The hydrochloric acid is stripped off in a rotary evaporator, and the product is dried at 50xc2x0 C. under reduced pressure and washed several times with ether. The hydrochlorides result as slightly colored crystals.
25.0 g of cyclooctylglycine hydrochloride were obtained starting from 18.9 g (150 mmol) of cyclooctanone. 26.6 g of 2-norbornylglycine hydrochloride were obtained starting from 16.5 g (150 mmol) of 2-norbornanone. 26.0 g of adamantylalanine hydrochloride were obtained starting from 19.7 g (120 mmol) of 1-formyladamantane. 16.6 g of xcex3-methylcyclohexylalanine hydrochloride were obtained starting from 12.6 g (100 mmol) of 1-formyl-1-methylcyclohexane. 25.9 g of 4-methylcyclohexylglycine hydrochloride were obtained starting from 16.8 g (150 mmol) of 4-methylcyclohexanone.
The amino acid hydrochlorides were converted by conventional processes using di-tert-butyl dicarbonate in water/dioxane into the Boc-protected form in each case and subsequently recrystallized from ethyl acetate/hexane mixtures or purified by column chromatography on silica gel (mobile phase: ethyl acetate/petroleum ether mixtures).
N-tert-Butyloxycarbonyl-(D)-xcex1-methyl-cyclohexylalanine
3.4 g (12.2 mmol) of Bcc-(D)-xcex1-methyl-Phe-OH were hydrogenated in 100 ml of MeOH at 50xc2x0 C. in the presence of 250 mg of 5% Rh on Al2O3 under 10 bar of hydrogen for 24 h. Filtration and stripping-off of the solvent resulted in 2.8 g of Boc-(D)-xcex1-Methyl-Cha-OH.
1H-NMR (DMSO-d6, xcex4 in ppm): 12 (very broad signal, COOH); 1.7-0.8 (25 H; 1.35 (s, Boc), 1.30 (s,Me))
Preparation of Boc-trimethylsilylalanine
The preparation took place both in optically active form as described by B. Weidmann, Chimica 46 (1992) 312 and in racemic form from N-(diphenylmethylene)glycine ethyl ester and trimethylsilylmethyl iodide.
N-tert-Butyloxy-(D,L)-trimethylsilylalanine
5.67 g (21.2 mol) of N-(diphenylmethylene)glycine ethyl ester in 35 ml of THF were deprotonated with a THF solution of LDA under standard conditions. To this were added dropwise at xe2x88x9270xc2x0 C. 5.0 g (23.4 mmol) of trimethylsilyl methyl iodide in 10 ml of THF, and the reaction mixture was allowed to rise slowly to Rt. Workup resulted in 7.2 g of N-(diphenylmethylene)trimethylsilylalanine ethyl ester, which was cleaved with 0.5 N HCl without further purification. The resulting hydrochloride was converted with NaHCO3 solution into 3.4 g of trimethylsilylalanine ethyl ester and converted under conventional conditions with di-tert-butyl dicarbonate into the Boc-protected compound almost quantitatively. The ethyl ester was hydrolyzed with dilute sodium hydroxide solution in methanol, the resulting salt was protonated with dilute hydrochloric acid, and the product was extracted with ethyl acetate/ether 1:1. 4.0 g of Boc-trimethylsilylalanine were obtained.
1H-NMR (DMSO-d6, xcex4 in ppm): xcx9c12 (very broad signal, COOH); 7.00 (d,1H,NH), 1.35 (s,9H,3 CH3), 0.95 (d,2H,CH2).
Boc-N-Cyclopropylglycine was prepared from N-cyclopropylglycine ethyl ester, ethyl bromoacetate and cyclopropylamine (similar to J. W. Skiles et al., J. Med. Chem. 35 (1992) 641) and then converted under standard conditions into the Boc-protected form, then hydrolyzed with MeOH/2N NaOH and finally acidified with 1N HCl.
Boc-Suberylglycine was synthesized in a similar way to the literature method (O. P. Goel et al. Tetrahedron Lett. 34 (1993) 953).
Adamantylglycine can also be prepared by the method of Y. N. Belokon et al. Zhu. Org. Khi, 21, (1985) 1327.
Boc-(3-Ph)-Pro-OH was synthesized by a method similar to that of J. Y. L. Chung et al. (J.Org.Chem. 55 (1990) 270).
Preparation of Boc-1-tetralinylglycine
Boc-1-Tetralinylglycine was prepared starting from 1,2-dihydronaphthalene, which was initially converted with HBr into 1-tetralyl bromide (similar to J. Med. Chem. 37 (1994) 1586). The bromide was then reacted with diethyl acetamidomalonate, and the xcex1-amino acid obtained after hydrolytic cleavage was converted under standard conditions into the Boc-protected form. Another possible preparation is described by E. Reimann and D. Voss (Arch. Pharm 310, (1977) 102).
Preparation of Boc-cycloleucine
Boc-Cycloleucine was prepared by the method of E. C. Jorgensen (J. Med. Chem. 14 (1971) 904).
Preparation of Boc-1-(D,L)-Tic-OH
Boc-1-(D,L)Tic-OH was prepared by a method of R. T. Shuman et al. (J. Med. Chem. 36 (1993) 314).
Preparation of Boc-(D,L)-Dch-OH
Boc-(D,L)-Dpa-OH (1 mmol) was hydrogenated in 12 ml of MeOH together with catalytic amount of 5% Rh/Al2O3 under 5 bar. Filtration and removal of the solvent under reduced pressure resulted in the product in quantitative yield.
Preparation of 4-isopropylcyclohexylglycine and 3,3-dimethylcyclohexylglycine
These amino acids were prepared by reacting the ketones 4-isopropylcyclohexanone and 3,3-dimethylcyclohexanone with ethyl isocyanoacetate by a method of H.-H. Prxc3xa4torius, J. Flossdorf and M. Kula (Chem. Ber. 108 (1975) 3079).
Boc-(D,L)-(3,4,5-(MeO)3)Phe-OH was prepared by alkylation of N-(diphenylmethylene)glycine ethyl ester with trimethyoxybenzyl chloride, followed by introduction of the Boc protective group and ester hydrolysis.
Preparation of Boc-D,L-Chea-OH
4.0 g of cycloheptylmethyl methanesulfonate (19.39 mmol), prepared from cycloheptylmethanol and methanesulfonyl chloride, were refluxed together with 4.9 g of N-(diphenylmethylene)glycine ethyl ester (18.47 mmol), 8.9 g of dry, finely powdered potassium carbonate (64.65 mmol) and 1 g of tetrabutylammonium bromide (3 mmol) in 50 ml of dry acetonitrile under an inert gas atmosphere for 10 h. The potassium carbonate was then filtered off, the filtrate was evaporated to dryness, and the crude product was immediately hydrolyzed with 20 ml of 2N hydrochloric acid in 40 ml of ethanol by stirring at RT for 1.5 h. The reaction solution was diluted and then benzophenone was extracted with ethyl acetate in the acid range, and subsequently H-D,L-Chea-OEt was extracted with DCM in the alkaline range (pHxe2x95x909), and the solution was dried over magnesium sulfate and evaporated in a rotary evaporator. Yield: 3.7 g≅95% of theory.
The conversion to Boc-D,L-Chea-OH took place in a conventional way via Boc-D,L-Chea-OC2H5 and subsequent ester hydrolysis.
Preparation of 4-tetrahydropyranylglycine
(a) 5-(4-Tetrahydropyranyl)hydantoin
90 g (0.774 mol) of 4-formyltetrahydropyran were added dropwise to a solution of 84.6 g (0.813 mol) of sodium bisulfite in 250 ml of water. The mixture was then diluted with 500 ml of ethanol and, at 20xc2x0 C., 300 g of ammonium carbonate and 100 g of potassium cyanide were added. The reaction mixture was stirred at 50xc2x0 C. for 5 h and at RT overnight.
For workup, the ethanol was stripped off under reduced pressure. The product was deposited in the form of colorless crystals after acidification of the aqueous phase with conc. hydrochloric acid. 141 g of the hydantoin were obtained.
(b) 4-Tetrahydropyranylglycine
10 g (54.3 mmol) of the hydantoin prepared above were heated with 25.7 g (81.5 mmol) of barium hydroxide in 130 ml of water under autogenous pressure in an autoclave at 165xc2x0 C. for 5 h. The resulting suspension was neutralized with dry ice at 50xc2x0 C. After cooling to 20xc2x0 C., the mixture was acidified with conc. sulfuric acid, and the barium sulfate precipitate was filtered off. The aqueous solution was neutralized with ammonia and left to stand for crystallization. 5.3 g of 4-tetrahydropyranylglycine were obtained.
(c) Boc-4-Tetrahydropyranylglycine
3.20 g (20.1 mmol) of 4-tetrahydropyranylglycine were Boc-protected with 4.39 g (20.1 mmol) of di-tert-butyl dicarbonate by a conventional process. Workup resulted in 4.8 g of Boc-4-tetrahydropyranylglycine. 1H-NMR (DMSO-d6, xcex4 in ppm) 12.5 (broad signal, 1H, COOH), 7.05 (d,1H,NH), 3.9-3.7 (3H, CH and 1H from each of 2CH2), 3.3-3.1 (2H, 1H from each of 2CH2), 1.85 (m, 1H, CH), 1.5-1.2 (13H, 2CH2 and Boc)
N-tert-Butyloxycarbonyl-(D,L)-4-tetrahydropyranylalanine
4-Bromomethyltetrahydropyran, which was prepared by reacting 4-hydroxymethyltetrahydropyran (see DE 92 42 33 430) with PBr3, and diethyl acetamidomalonate, previously deprotonated with NaH in DMF, were converted into diethyl acetamido(4-tetrahydropyranylmethyl)malonate, and the esters and the acetyl group were then hydrolyzed, with simultaneous decarbonylation, with 6N HCl and glacial acetic acid at 100xc2x0 C. to give 4-tetrahydropyranylalanine hydrochloride.
The amino group was protected with a Boc group by a process known from the literature. The crude product was taken up in ethyl acetate, extracted with 0.5N NaOH, the aqueous phase was acidified with 1N HCl, and the product was extracted with DCM. After drying over Na2SO4, the solvent was completely stripped off. Pure N-tert-butyloxycarbonyl-(D,L)-4-tetrahydropyranylalanine was obtained.
1H-NMR (DMSO-d6, xcex4 in ppm): 12.5 (broad signal, 1H, COOH), 7.10 (d, 1H, NH), 3.95 (m, 1H), 3.80 (m, 2H, 1H from each of 2 CH2 groups), 3.20 (m, 2H, 1H from each of 2 CH2 groups), 1.75-1.0 (16H, 3xc3x97CH2, CH and Boc).
Hydroxyacetic acid derivatives were prepared either by methods similar to that of S. Bajusz (WO 93/18060) or starting from corresponding methyl acetate derivatives by xcex1-hydroxylation using Davis"" reagent (F. A. Davis, L. C. Vishwakarma, J. M. Billmers J. Org. Chem. 49 (1984) 3241).
The H2Nxe2x80x94C(R1R2)xe2x80x94Dxe2x80x2 building blocks were prepared in the following way:
1. Preparation of 6-cyano-3-picolylamine:
(a) 6-Cyano-3-picolyl azide
14.5 g (0.07 mol) of TFAA dissolved in 20 ml of DCM were added dropwise to a solution of 8.8 g (0.07 mol) of 6-cyano-3-picolyl alcohol and 6.9 g of TEA in 200 ml of DCM at RT and the mixture was then stirred for 2 h. The residue after removal of the DCM by distillation was dissolved in a mixture of toluene and 50 ml of DMSO, 11.2 g (0.17 mol) of NaN3 and 0.7 g of TBAB were added, and the mixture was stirred at RT overnight.
The reaction mixture was poured into 300 ml of water and extracted several times with ether. After drying with Na2SO4 and removal of the solvent under reduced pressure, 6.8 g of yellowish crystals remained and were used without further purification in the next reaction.
(b) 6-Cyano-3-picolylamine
The compound obtained in (a) was dissolved in 45 ml of THF and 1.2 ml of water and, while stirring, 11.2 g of triphenylphosphine were added in portions. The reaction mixture was left to stand at RT overnight.
After removal of the solvent by distillation, the residue was taken up in 100 ml of ether, the precipitated triphenylphosphine oxide was filtered off with suction, and the filtrate was adjusted to pH 2 with ethereal hydrochloric acid. The precipitated hydrochloride was filtered off with suction, washed with ether and digested successively with toluene and hot isopropanol. 4.7 g of hydrochloride were isolated, melting point 253-256xc2x0 C. (decomposition).
2. Preparation of 5-aminomethyl-2-cyanopyrimidine:
(a) 2-Methylthio-5-hydroxycarbonylpyrimidine
1 Eq. of 2-methylthio-5-ethoxycarbonylpyrimidine were dissolved in dioxane and, after addition of 2 eq. of 2N LiOH, stirred overnight. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOH. After addition of a stoichiometric amount of ethereal HCl, the solution was again evaporated to dryness. Water which was still present was removed by azeotropic drying with toluene once.
(b) 2-Methylthio-5-hydroxymethylpyrimidine
The acid obtained in 2.(a) was reduced to the alcohol by a method of A. I. Meyers et al. (Org. Synth. Coll. Vol. VII, 530). Yield: 40%. FAB-MS (M+)=156
(c) 2-Methylthio-5-aminomethylpyrimidine
The resulting alcohol was converted into the amine and isolated as hydrochloride as described above. Yield: 30%. FAB-MS (M+)=155
(d) N-Boc-5-aminomethyl-2-methylthiopyrimidine
5-Aminomethyl-2-methylthiopyrimidine hydrochloride was protected with a Boc group under standard conditions (see M. Bodanszky, A. Bodanszky xe2x80x9cThe Practice of Peptide Synthesisxe2x80x9d, 2nd edition, Springer Verlag Heidelberg, 1994). Yield: 73%. FAB-MS (M+)=255
(e) N-Boc-5-aminomethyl-2-methylsulfonylpyrimidine
1 Eq. of N-Boc-5-aminomethyl-2-methylthiopyrimidine was introduced into acetic acid at 70-80xc2x0 C. Then 2.5 eq. of H2O2 (50% strength) were slowly added dropwise. After conversion of the precursor was complete, the reaction mixture was concentrated to one third of the volume and poured into water. The precipitated solid was filtered off and dried in a desiccator over phosphorus pentoxide. Yield: 37%. FAB-MS (M+)=283
(f) N-Boc-5-aminomethyl-2-cyanopyrimidine
1 Eq. of N-Boc-5-aminomethyl-2-methylsulfonylpyrimidine was dissolved in DMF and introduced into a reflux apparatus. After addition of 2 eq. of KCN and catalytic amounts of 18-crown-6, the reaction mixture was stirred at 60xc2x0 C. for 4 h. The suspension was then concentrated and poured into 200 ml of water. The precipitated solid was filtered off with suction and dissolved in ethyl acetate. The solution was washed with water and saturated NaCl solution, dried and evaporated in a rotary evaporator. N-Boc-5-aminomethyl-2-cyanopyrimidine was used as crude product without further purification in the next reaction. Yield: 46%.
(g) 5-Aminomethyl-2-cyanopyrimidine hydrochloride
1 Eq. of N-Boc-5-aminomethyl-2-cyanopyrimidine was introduced into dioxane at RT and, after addition of dioxane/HCl (5M), stirred at RT for 3 h. After conversion of the precursor was complete (TLC check: mobile phase A), the reaction mixture was concentrated and poured into ether. The precipitated solid was filtered off with suction, again dissolved in MeOH and poured into ether. The product was filtered off with suction and dried under high vacuum to afford 89% of the theoretical yield of 5-aminomethyl-2-cyanopyrimidine hydrochloride. FAB-MS (M+)=134
3. Preparation of 4-aminomethyl-3-methoxybenzonitrile
(a) 3-Nitro-4-methylbenzonitrile
399 g (2.56 mol) of p-toluonitrile were added over the course of 90 minutes to 1 l of fuming nitric acid at xe2x88x9210xc2x0 C. 1 h after the addition, the mixture was poured onto 2.5 l of ice/H2O, whereupon a solid precipitated and was removed on a suction filter funnel and washed to neutral pH with water. The yield of the product was 363 g (88%). 1H-NMR (CDCl3; xcex4 in ppm): 8.3 (d, 1H); 7.8 (dd, 1H); 7.5 (dd, 1H); 2.7 (s, 3H)
(b) 3-Amino-4-methylbenzonitrile:
120 g of 3-nitro-4-methylbenzonitrile were suspended in 1.2 l of EtOH and hydrogenated with 50 l of hydrogen at RT in the presence of 7 g of Pd/C (10%). After removal of the catalyst on Celite, the solvent was stripped off to result in 95 g of pure product (97%). 1H-NMR (DMSO-d6; xcex4 in ppm): 7.1 (dd, 1H); 6.90 (d, 1H); 6.85 (dd, 1H); 5.35 (s, 2H, NH2); 2.15 (s, 3H)
(c) 3-Hydroxy-4-methylbenzonitrile:
A solution of 49.2 g (0.72 mol) of NaNO2 in 217 ml of water was added dropwise over the course of 30 min to 85 g (0.72 mol) of 3-amino-4-methylbenzonitrile in 1.8 l of 6N HCl at 0-5xc2x0 C. The mixture was then stirred at 0-5xc2x0 C. for a further 30 min and then at the boiling point for 1 h. After the solution had cooled it was possible to extract the product with ethyl acetate and, from this, the phenolate with ice-cold 5N NaOH. The aqueous phase was then acidified to pH 3 with 6N HCl and the product was extracted with ethyl acetate. 41 g (43%) of the phenol were obtained. 1H-NMR (DMSO-d6; xcex4 in ppm): 10.3 (s, OH); 7.25 (dd, 1H); 7.15 (d, 1H); 7.1 (dd, 1H); 2.20 (s, 3H)
(d) 3-Methoxy-4-methylbenzonitrile:
15 g (0.11 mol) of 3-hydroxy-4-methylbenzonitrile dissolved in 30 ml of DMF were added dropwise to a suspension of 0.11 mol of NaH and 30 ml of DMF, and the mixture was stirred until no further H2 evolution was observed. Then 10.6 ml (0.17 mol) of methyl iodide were added dropwise, and the mixture was stirred at RT for 1 h. The solution was poured into ice-water, and the product was extracted with ether/ethyl acetate 7:1. After the solvent had been stripped off, the product began slowly to crystallize. 14.8 g (89%) of the product were obtained. 1H-NMR (CDCl3; xcex4 in ppm): 7.2 (m, 2H); 7.02 (s, 1H); 3.85 (s, 3H); 2.25 (s, 3H)
(e) 4-Bromomethyl-3-methoxybenzonitrile:
14.7 g (0.1 mol) of 3-methoxy-4-methylbenzonitrile were dissolved in 210 ml of 1,2-dichloroethane, bromination was carried out at 82xc2x0 C. in the presence of catalytic amounts of AIBN with 19.1 g (0.11 mol) of NBS in portions over the course of 1 h and, after the addition was complete, the mixture was stirred at 82xc2x0 C. for a further 30 min. Addition of n-heptane was followed by removal of precipitated succinimide, and the solvent was stripped off. The product contained, besides small amounts of precursor, also traces of the corresponding benzal bromide. 1H-NMR (DMSO-d6; xcex4 in ppm): 7.60 (dd, 1H); 7.50 (d, 1H); 7.40 (dd, 1H); 4.68 (s, 2H); 3.96 (s, 3H)
(f) 4-Phthalimidomethyl-3-methoxybenzonitrile:
24.4 g (108 mol) of 4-bromomethyl-3-methoxybenzonitrile dissolved in 125 ml of DMF and 20.0 g of potassium phthalimide were stirred at RT for 24 h and then at 50xc2x0 C. for 1 h. The mixture was poured into water, whereupon the product precipitated as solid. 21.5 g (68%) of the product were obtained. 1H-NMR (DMSO-d6; xcex4 in ppm): 7.9 (m, 4H); 7.5 (d, 1H); 7.35-7.25 (m, 2H); 7.78 (s, 2H); 3.92 (s, 3H)
(g) 4-Aminomethyl-3-methoxybenzonitrile:
10.6 ml of hydrazine hydrate were added to 21.2 g (73 mmol) of 4-phthalimidomethyl-3-methoxybenzonitrile dissolved in 290 ml of THF, and the mixture was stirred at RT for 20 h. Then 180 ml of 2N HCl were added dropwise and, after 1.5 h, the solvent was completely stripped off. The residue was taken up in MTBE, extracted with 1N HCl, adjusted to pH 9-10 with 2N NaOH and extracted with DCM. 8.0 g (68%) of the product were obtained. 1H-NMR (DMSO-d6; xcex4 in ppm): 7.55 (dd, 1H); 7.40 (dd, 1H); 7.37 (d, 1H); 3.85 (s, 3H); 3.70 (s, 2H); 2.5-1.6 (NH2).
4. Preparation of 4-aminomethyl-3-ethoxybenzonitrile:
(a) 3-Ethoxy-4-methylbenzonitrile
10 g (75 mmol) of 4-methyl-3-hydroxybenzonitrile were deprotonated with 1 eq. of NaH in 100 ml of DMF and then ethylated on the oxygen with 112 mmol of iodoethane. 8.8 g of product were obtained.
1H-NMR (DMSO-d6, xcex4 in ppm): 7.4-7.25 (3H), 4.10 (q, 2H), 2.22 (s, 3H), 1.35 (t, 3H)
(b) 4-Bromomethyl-3-ethoxybenzonitrile
Preparation took place as in Example 3.(e) with NBS. 1H-NMR (DMSO-d6, xcex4 in ppm): 7.59 (1H), 7.50 (1H), 7.40 (1H), 4.65 (s, 2H), 4.20 (q, 2H), 1.35 (t, 3H)
(c) 4-Aminomethyl-3-ethoxybenzonitrile hydrochloride
Synthesis took place via the stage of the corresponding phthalimide as in Example 3.(f) and to give the hydrochloride product by cleavage with hydrazine and treatment with HCl as in Example 3.(g). Starting from 10 g of precursor (a), 5.1 g of the product were obtained. 1H-NMR (DMSO-d6, xcex4 in ppm): 8.5 (broad signal, NH3+), 7.65-7.45 (3H), 4.18 (q, 2H), 4.05 (s, 2H), 1.38 (t, 3H).
5. Preparation of 4-aminomethyl-3-benzyloxybenzonitrile:
(a) 3-Benzyloxy-4-hydroxymethylbenzonitrile
33.1 g of 4-formyl-3-hydroxybenzonitrile (Liebigs Ann. Chem. (1982) 1836) were O-benzylated with 1 eq. each of benzyl bromide and K2CO3 and, after workup, reduced with NaBH4 in 100 ml of MeOH/THF 2:3 at xe2x88x9210xc2x0 C. to 0xc2x0 C. to give the alcohol. 22.4 g were obtained. The product could be crystallized from DCM/petroleum ether. 1H-NMR (CDCl3, xcex4 in ppm): 7.48 (1H), 7.40-7.3 (5H), 7.20 (1H), 7.08 (1H), 5.05 (s, 2H), 4.75 (s, 2H), 2.85 (1H, OH)
(b) 3-Benzyloxy-4-bromomethylbenzonitrile:
4.3 g (18 mmol) of the alcohol (a) underwent substitution in 40 ml of THF with 7.9 g (24 mmol) of CBr4 and 6.3 g (24 mmol) of PPh3, which was added in portions over the course of 30 min. The reaction mixture was stirred at RT for 20 h. The product was purified by column chromatography (mobile phase: t-butyl methyl ether/petroleum ether 2:1). 4.6 g were obtained. 1H-NMR (DMSO-d6, xcex4 in ppm): 7.70-7.25 (8H), 5.30 (s, 2H), 4.70 (s, 2H)
(c) 4-Aminomethyl-3-benzyloxybenzonitrile
Synthesis took place via the stage of the corresponding phthalimide as in Example 3.(f). The hydrazine cleavage was carried out as in Example 3.(g). The free amine was generated at pH 9-10 from the initially produced hydrochloride and was extracted from the aqueous solution with ether. 1H-NMR (DMSO-d6, xcex4 in ppm): 7.65-7.25 (8H), 5.20 (s, 2H), 3.80 (s, 2H), ca. 3.0 (broad signal, NH2)
6. Preparation of 4-aminomethyl-3-iodobenzonitrile:
(a) 3-Iodo-4-methylbenzonitrile
25.3 g (0.15 mol) of 3-amino-4-methylbenzonitrile hydrochloride (Example 3.(b)) were converted in a Sandmeyer reaction into 22.1 g of product. 1H-NMR (DMSO-d6, xcex4 in ppm): 8.30 (1H), 7.78 (1H), 7.50 (1H), 2.45 (3H)
(b) 4-Bromomethyl-3-iodobenzonitrile
Preparation took place as in Example 3.(e) with NBS. 1H-NMR (DMSO-d6, xcex4 in ppm): 8.38 (1H), 7.89 (1H), 7.77 (1H), 4.78 (2H)
(c) 4-Aminomethyl-3-iodobenzonitrile hydrochloride
12.1 g (37.6 mmol) of 4-bromomethyl-3-iodobenzonitrile in 200 ml of MeOH/THF 1:1 were slowly added dropwise to 200 ml of conc. ammonia solution/MeOH (saturated with NH3) 1:1, simultaneously passing NH3 into the reaction mixture. The temperature was maintained at 50xc2x0 C. After 4 h, the solvent was stripped off, and the product was taken up in DCM, dried and precipitated with ethereal HCl. 8.6 g of 4-aminomethyl-3-iodobenzonitrile hydrochloride were obtained. 1H-NMR (DMSO-d6, xcex4 in ppm): 8.8 (broad signal, NH3+), 8.43 (1H), 7.98 (1H), 7.70 (1H), 4.13 (2H)
7. Preparation of 4-aminomethyl-2-methoxybenzonitrile:
(a) 2-Methoxy-4-methylbenzonitrile
10.7 g (78.6 mmol) of 4-methylsalicylaldehyde (J. C. S. Perkin I (1980) 1862) were methylated with 5.8 ml of MeI in the presence of 13 g of K2CO3 in 40 ml of DMF. The reaction mixture was poured into ice-water, and the product (11.5 g) was extracted with ether. The aldehyde was converted into the nitrile by a method similar to that in Synthesis (1978) 11. 1H-NMR (DMSO-d6, xcex4 in ppm): 7.60 (d, 1H), 7.05 (s, 1H), 6.90 (d, 1H), 3.90 (s, 3H), 2.40 (s, 3H)
(b) 4-Bromomethyl-2-methoxybenzonitrile
4.6 g (31.3 mmol) of 4-methyl-2-methoxybenzonitrile were brominated with 34.7 mmol of N-bromosuccinimide in the presence of catalytic amounts of azobisisobutyronitrile in 60 ml of 1,2-dichloroethane under reflux. 2.5 g of the product were obtained. 1H-NMR (DMSO-d6, xcex4 in ppm): 7.75 (d, 1H), 7.35 (s, broad, 1H), 7.15 (d, broad, 1H), 4.73 (s, 2H), 3.95 (s, 3H)
(c) 4-Aminomethyl-2-methoxybenzonitrile
2.5 g of the bromide (b) were introduced into 10 ml of MeOH, and NH3 was passed in during dropwise addition of 38 ml of conc. ammonia/MeOH 1:1. After 2 h, the solvent was stripped off, the product was taken up in DCM and washed with water, and the organic phase was dried over Na2SO4. The product was precipitated as hydrochloride with ethereal HCl. 1H-NMR (DMSO-d6, xcex4 in ppm): 8.6 (broad signal, NH3+), 7.79 (1H), 7.55 (1H), 7.20 (1H), 4.10 (s, 2H), 3.93 (s, 3H)
8. Preparation of 4-aminomethyl-2-benzyloxybenzonitrile:
(a) 2-Benzyloxy-4-hydroxymethylbenzonitrile
41 ml (41 mmol) of a 1 molar BBr3 solution in DCM were added dropwise to 5.5 g (37.4 mmol) of 2-methoxy-4-methylbenzonitrile (Example 7(a)) in 100 ml of DCM at 0xc2x0 C., and the mixture was stirred at 0xc2x0 C. for 1 h and at RT for a further 2 days. The mixture was poured into 10% strength ammonia solution, and the 2-hydroxy-4-methylbenzonitrile was extracted with DCM. The formyl group was generated from the methyl group by the method in Liebigs Ann. Chem. (1982) 1836, and the 4-formyl-2-hydroxybenzonitrile was converted into 2.1 g of 2-benzyloxy-4-hydroxymethylbenzonitrile as in Example 5.(a).
(b) 4-Aminomethyl-2-benzyloxybenzonitrile
2.1 g (8.8 mmol) of the benzyl alcohol (a) were converted as in Example 5.(b) with CBr4 and PPh3 into 2.2 g of 2-benzyloxy-4-bromomethylbenzonitrile. The benzylamine was synthesized as in Example 3.(f) and 3.(g) via the stage of the phthalimide to give 4-aminomethyl-2-benzyloxybenzonitrile.
9. Preparation of 4-aminomethyl-2-chlorobenzonitrile:
11.75 g (77.2 mmol) of 4-methyl-2-nitroaniline underwent a Sandmeyer reaction in a conventional process by diazotization and substitution with NaCN and CuSO4 to give 9.6 g of crude 4-methyl-2-nitrobenzonitrile. 1H-NMR (DMSO-d6, xcex4 in ppm): 8.25 (1H), 8.05 (1H), 7.80 (1H), 2.50 (3H)
The nitro group was hydrogenated as in Example 3.(b), and the resulting 2-amino-4-methylbenzonitrile was subjected to another Sandmeyer reaction to give 2-chloro-4-methylbenzonitrile. The subsequent reactions to give 4-bromomethyl-2-chlorobenzonitrile, 2-chloro-4-phthalimidomethylbenzonitrile and finally 4-aminomethyl-2-chlorobenzonitrile took place as in Examples 3.(e), 3.(f) and 3.(g).
10. Preparation of 6-carbamoyl-3-picolylamine dihydrochloride:
67 g (0.46 mol) of 5-cyanopyridine-2-carboxamide (Chem. Ber. 117 (1984) 1259) were suspended in 1 l aqueous methanol (1/1) and 84.7 ml (1.9 equivs.) of conc. HCl, 21,4 g of 10% strength Pd/C were added and hydrogenation was carried out in a shaken vessel at room temperature for 5 h (H2 uptake: 23.2 l; theory: 22.3 l). The product dissolved during the hydrogenation (and the catalyst changed from gray to black). TLC (CH2Cl2/MeOH 9/1, NH3-saturated) revealed only traces of starting material.
The catalyst was filtered off with suction and washed with water, and the filtrate was evaporated under reduced pressure, finally with the addition of toluene and ethanol.
The moist residue was briefly refluxed in about 400 ml of MeOH, after cooling and stirring in an ice bath for about 30 minutes, filtered off with suction and washed with methyl t-butyl ether.
78 g (76.5%) of dihydrochloride were isolated as white crystals, melting point greater than 260xc2x0 C.